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Biomedical subjects

M Boeckh

Publications and source records attributed to M Boeckh.

At least 37 records · Page 2Linked to original sources
PubMed1999

Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation.

High-dose therapy with autologous peripheral blood stem cell (PBSC) rescue is widely used for the treatment of malignant disease. CD34 selection of PBSC has been applied as a means of reducing contamination of the graft. Although CD34 selection results in a 2 to 3 log reduction in contaminating tumor cells without significantly delaying engraftment, many other types of cells are depleted from the CD34-enriched grafts and immune reconstitution may be impaired. In the present study, 31 cytomegalovirus (CMV)-seropositive patients who received myeloablative therapy followed by the infusion of CD34-selected autologous PBSC were assessed for the development of CMV disease in the first 100 days posttransplant. Seven patients (22.6%) developed CMV disease and 4 patients (12.9%) died from complications of their infection. In a contemporaneous group of 237 CMV-seropositive patients receiving unselected, autologous PBSC, only 10 patients (4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate logistic regression analysis, the use of CD34-selected autologous PBSC after high-dose therapy was associated with a marked increase in the incidence of CMV disease and CMV-associated deaths.

Adolescent↗
PubMed1999

Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy.

Cytomegalovirus (CMV) remains a cause of significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Ganciclovir prophylaxis, or preemptive treatment based on detection of antigenemia or CMV DNA by PCR, effectively prevents CMV disease during the first 100 days after transplant in allograft recipients. In recipients of T-cell depleted transplant or if severe acute graft-versus-host disease is present, ganciclovir prophylaxis or preemptive treatment should be started with an induction course of ganciclovir (5 mg/kg BID) and given at least 5 days per week and continued until day 100 after transplant. Although prevention of CMV disease before day 100 is highly effective, there is a continued risk of late-onset CMV disease after day 100. In CMV-seropositive recipients, the incidence of late CMV disease may be as high as 17%. Strategies to prevent late CMV infection and disease are needed. In seronegative recipients, seronegative or leukocyte-reduced blood products are effective in preventing acquisition of CMV through blood products. Controversy exists about the optimal strategy of preventing CMV disease in seropositive autologous HSCT recipients. The outcome of CMV pneumonia remains poor despite treatment with ganciclovir in combination with CMV hyperimmune globulin or intravenous immunoglobulin. Owing to continued clinical significance of CMV in the HSCT setting, new and more effective anti-CMV drugs with improved pharmacokinetic properties are urgently needed.

Antibodies, Monoclonal↗
PubMed1999

High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis.

Chemoprophylaxis for Pneumocystis carinii pneumonia (PCP) is routinely given after allogeneic blood or marrow transplantation. We evaluated the effectiveness of dapsone prophylaxis (50 mg orally twice daily, 3 times per week) compared with twice-weekly trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing PCP after allogeneic blood or marrow transplantation. Patients included all (n=646) who received allogeneic blood or marrow transplants between 1 September 1993 and 31 December 1996 who survived at least 100 days after transplantation. A cohort of 111 dapsone recipients was compared with the remaining 535 who received TMP-SMZ. Ten patients developed PCP; 8 were taking dapsone. PCP incidence in the TMP-SMZ cohort was 0.37% versus 7.2% for dapsone. The relative risk for PCP associated with dapsone use was 18.8 (P<.001) and was not accounted for by age, clinical extensive chronic graft-versus-host disease, donor source, or malignant relapse. Dapsone prophylaxis at this dosage is associated with significantly higher rates of PCP than is TMP-SMZ after allogeneic marrow transplantation. We advise caution in prescribing alternatives to TMP-SMZ prophylaxis in this setting.

Adult↗
PubMed1999

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Journal Article↗
PubMed1998

A study of the pharmacokinetics, antiviral activity, and tolerability of oral ganciclovir for CMV prophylaxis in marrow transplantation.

Oral ganciclovir is effective in preventing cytomegalovirus (CMV) disease in HIV-infected patients despite a bioavailability of only 6-9%. To determine safety, pharmacokinetics, and the influence of acute gastrointestinal graft-vs.-host disease (GI-GVHD) on the bioavailability and antiviral effect of oral ganciclovir after marrow transplantation, CMV seropositive patients received oral ganciclovir (1000 mg 3 times per day) from day 35 (+/- 7 days) until day 100 after transplantation. Single-dose (intravenous and oral) and steady-state oral pharmacokinetic profiles and weekly trough levels were performed. Twenty-one patients received oral ganciclovir (seven with GI-GVHD, 14 without); 17 had steady-state pharmacokinetic profiles and seven had single-dose profiles. The absolute bioavailability was similar in patients with or without acute GI-GVHD (7.2 vs. 6.9%). At steady state, the extent and rate of absorption of oral ganciclovir were comparable in these same patient subgroups (area under the curve [AUC] = 13.5 and 10.2 mg x hours/L, respectively; time to peak serum ganciclovir concentrations = 5.5 and 3.8 hours, respectively). Breakthrough CMV antigenemia, viremia, or plasma polymerase chain reaction positivity occurred in eight of 21 (38%) patients (four of seven with GVHD and four of 14 without). Drug discontinuation because of GI adverse effects was required in six of 21 (29%) patients. Neutropenia occurred in two of 15 (13%) patients who had received oral ganciclovir for more than 10 days. In conclusion, the bioavailability of oral ganciclovir seems similar to that reported in other settings. The presence of acute GVHD of the GI tract did not appear to adversely affect absorption of oral ganciclovir. The use of oral ganciclovir was limited by the presence of GI intolerance in the early posttransplant period. The efficacy of oral ganciclovir in preventing CMV infection in marrow transplant recipients is being assessed in a separate randomized controlled trial.

Administration, Oral↗
PubMed1998

Effect of high-dose acyclovir on survival in allogeneic marrow transplant recipients who received ganciclovir at engraftment or for cytomegalovirus pp65 antigenemia.

This study sought to determine whether high-dose acyclovir improves posttransplant survival in cytomegalovirus (CMV)-seropositive patients when ganciclovir is given for prophylaxis or as early therapy. Three groups were studied: Group 1 (n = 112) received ganciclovir from engraftment without prior acyclovir treatment, group 2 (n = 114) was given ganciclovir for CMV pp65 antigenemia without prior acyclovir, and group 3 (n = 133) received ganciclovir at engraftment with prior intravenous acyclovir (500 mg/m2 every 8 h) from day 5 before transplant until engraftment. In a multivariable Cox model, there was no significant difference in the adjusted risk of transplant survival between the groups during the first 2 years after transplant (relative risk for mortality: group 1, 1.0; group 2, 0.75 (95% confidence interval [CI], 0.52-1.1); group 3, 1.04 (95% CI, 0.74-1.47). The incidence of CMV disease and CMV-related mortality was not significantly different between the groups. Thus, high-dose acyclovir does not appear to improve survival when ganciclovir is given either at engraftment or for CMV pp65 antigenemia.

Acyclovir↗
PubMed1998

Quantitation of cytomegalovirus: methodologic aspects and clinical applications.

Cytomegalovirus (CMV) is an important pathogen in transplant recipients and human immunodeficiency virus (HIV)-infected individuals. Major progress has been made in developing quantitative detection methods for CMV in recent years. Due to their high sensitivity, these assays can detect CMV early, and quantitation may be useful in predicting the patient's risk for disease and in monitoring the effect of antiviral therapy. This review discusses methodological aspects of currently used quantitative assays for CMV (i.e., viral culture techniques, antigen detection assays, DNA detection assays including PCR, branched-DNA assay, and the DNA hybrid capture assay) and addresses the correlation of systemic and site-specific CMV load and CMV disease in different populations of immunosuppressed patients as well as the response to antiviral treatment. To date, direct antigen detection and molecular techniques have largely replaced traditional culture-based techniques for CMV quantitation. In general, a high systemic CMV load is correlated with CMV disease. This correlation is strong in the HIV-infected population and in solid-organ transplant recipients but less clear in allogeneic marrow transplant recipients. Measuring the viral load at specific anatomic sites may be an alternative way to assess disease activity in situations where the systemic viral load correlates poorly with disease activity. A reduction of the systemic CMV load also correlates with a response to antiviral treatment, but more research is needed to evaluate the role of viral load as a surrogate marker for drug resistance. Due to the widespread use of quantitative CMV detection techniques to direct and monitor antiviral treatment, there is a great need for an assessment of the reproducibility of test results and better standardization of the assays.

AIDS-Related Opportunistic Infections↗
PubMed1997

Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome.

To determine risk factors, frequency, time patterns, and outcome of ganciclovir-related neutropenia in allogeneic marrow transplant recipients, 278 consecutive patients receiving ganciclovir from engraftment until day 100 were studied. In this cohort, 159 patients (57%) had absolute neutrophil counts (ANC) less than 1,500/microL, 112 (41%) had an ANC less than 1,000/microL, 87 (31%) less than 750/microL, and 56 (21%) less than 500/microL for at least 2 consecutive days. Statistically significant risk factors for neutropenia in a Cox model were low marrow cellularity between day 21 and 28 (relative risk [RR] 2.4, P = .0002), hyperbilirubinemia > or =6 mg/dL during the first 20 days (RR 2.5, P = .0001), and elevation of serum creatinine > or =2 mg/dL after day 21 after transplant (RR 2.1, P = .001). Restriction to factors present at engraftment resulted in a similar model with low marrow cellularity, hyperbilirubinemia > or =6 mg/dL, and elevated serum creatinine as significant risk factors. Patients with no risk factor had an incidence of neutropenia of 21%, an incidence of 31% for one risk factor, and of 57% for two or more risk factors (RR 3.8, P = .001). Neutropenia was a negative predictor of overall (RR 2.0, P = .0001) and event-free survival (RR 2.1, P < .0001), and a predictor of relapse (RR 1.7, P = .03) and nonrelapse mortality (RR 2.1, P = .003). Thus, early liver dysfunction, elevated serum creatinine, and low marrow cellularity are risk factors for ganciclovir-related neutropenia. Neutropenia in ganciclovir recipients after marrow transplantation is an independent risk factor for mortality.

Adolescent↗
PubMed1997

Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation.

A retrospective analysis of cytomegalovirus (CMV) genotype was conducted on 281 CMV isolates obtained from marrow transplant recipients. The genotyping was based on sequence variations in the gene encoding envelope glycoprotein B (gB) as detected by restriction analysis of polymerase chain reaction (PCR)-amplified gB DNA. Among all isolates studied, the distribution of gB types 1-4 was 48.4%, 16.4%, 24.6%, and 8.2%, respectively, with only 2.5% of all isolates containing more than one gB type. The association of gB types with acute graft-versus-host-disease (GVHD) and death related to myelosuppression was examined using appropriate multivariable regression models. Covariables in addition to gB type included underlying disease type, donor-recipient HLA matching, donor CMV serostatus, and age as a continuous variable. Death associated with myelosuppression occurred in 2.9% or 4 of 136 patients with gB1, 0% or 0 of 46 patients with gB2, 21.7% or 15 of 69 patients with gB3, and 17.4% or four of 23 patients with gB4. The significant association of CMV gB type with death due to myelosuppression was maintained in a multivariable analysis (P < .001). In addition, the data also suggested that gB types 3 and 4 may be associated with a reduced hazard of grades II to IV acute GVHD.

Adult↗
PubMed1997

Plasma polymerase chain reaction for cytomegalovirus DNA after allogeneic marrow transplantation: comparison with polymerase chain reaction using peripheral blood leukocytes, pp65 antigenemia, and viral culture.

In a prospective longitudinal study, detection of cytomegalovirus (CMV) DNA in plasma (plasma polymerase chain reaction [PCR]) was compared with PCR of CMV DNA in peripheral blood leukocytes (PBL PCR), the CMV pp65 antigenemia assay, and viral cultures from blood, urine, and throat of 29 patients, 14 of whom received pp65 antigenemia-guided early ganciclovir treatment and 15 of whom received ganciclovir at engraftment. Among 328 blood samples tested by all methods, PBL PCR was the most sensitive test, followed by the pp65 antigenemia assay, plasma PCR, and viremia. In the 14 patients who received pp65 antigenemia-guided early treatment, the incidence of PBL PCR, pp65 antigenemia, plasma PCR, and viremia before day 100 was 79%, 79%, 71%, and 27%, respectively, with a median day of onset of day 32, 42, 45, and 51, respectively. Nine patients (64%) became positive by PBL PCR, pp65 antigenemia, and plasma PCR. Of 15 patients who were treated with ganciclovir at engraftment, 12 (80%) became positive by PBL PCR, plasma PCR, and/or pp65 antigenemia while receiving ganciclovir; 3 (20%) had breakthrough infection with all three methods, including 2 with high-grade antigenemia (more than three positive cells in duplicate staining); none of these patients subsequently developed positive CMV cultures or disease. In 49 specimens, PBL PCR and/or pp65 antigenemia assay could not be performed because of insufficient neutrophil counts. In conclusion, the sensitivity of plasma PCR is significantly lower than that of PBL PCR but similar to that of the pp65 antigenemia assay. Plasma PCR may be particularly useful in clinical situations in which a less sensitive and possibly more specific assay is warranted or in which leukocyte counts are inadequate to perform cell-based assays.

Antigens, Viral↗
PubMed1997

Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial.

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day -1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving > or =28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

Adolescent↗
PubMed1997

Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation.

BACKGROUND: The aim of our study was to describe the incidence, clinical course, and risk factors for the idiopathic pneumonia syndrome (IPS), compared with those previously described for "idiopathic pneumonia," after bone marrow transplantation (BMT). METHODS: Our study design was a case-series review with determination of risk by comparison with unaffected controls by log-rank or Fisher's exact (two-tailed) test and logistic regression analyses. The study group comprised 1165 consecutive marrow recipients at a single center from 1988 to 1991. RESULTS: IPS was documented in 85 BMT recipients (7.3%) by bronchoalveolar lavage (n=68), open lung biopsy (n=3), or autopsy (n=14). The calculated actuarial incidence for IPS within 120 days after BMT was 7.7%. Median time to onset was 21 days (mean 34+/-30). Hospital mortality was 74%, and 53 BMT recipients (62%) died with progressive respiratory failure. IPS resolved in 22 patients (26%); 18 patients (21%) survived to discharge. Mechanical ventilation was required by 59 BMT recipients (69%), within a median of 2 days of onset of infiltrates. Two of these 59 recipients (3%) survived to discharge. Pulmonary infection (predominantly fungal) was noted in 7 of 25 (28%) BMT recipients who had an autopsy. Potential risk factors for IPS were assessed in univariate and multivariate logistic regression analyses. Although the incidence was not significantly different between autologous (5.7%) and allogeneic marrow recipients (7.6%), risks were identified only for the latter: malignancy other than leukemia (odds ratio=6.5 compared with aplastic anemia), and grade 4 graft-versus-host disease (odds ratio=5.4 compared with lower grades). No factors were associated with recovery. CONCLUSIONS: The incidence of idiopathic lung injury seems lower, the onset earlier, and the risk factors different from those previously reported. The major risks seem to be regimen-related toxicity and multi-organ dysfunction associated with alloreactive processes.

Adult↗
PubMed1997

Circulating cytomegalovirus (CMV)-infected endothelial cells in marrow transplant patients with CMV disease and CMV infection.

Circulating cytomegalovirus (CMV)-infected endothelial cells (CCIC) have been found in immunocompromised patients with CMV disease and have been associated with disease severity. The frequency of CCIC in marrow transplant recipients was studied to determine its use for distinguishing between CMV pneumonia and asymptomatic CMV infection. CCIC were found in 13 (81%) of 16 patients with CMV pneumonia (5/6 without copathogen; 7/10 with copathogen) and in 10 (50%) of 20 patients with asymptomatic CMV antigenemia at different levels. There was no statistically significant association for the incidence nor the quantitative level of CCIC in patients with asymptomatic CMV antigenemia, CMV pneumonia with or without copathogen, or different levels of CMV virus load measured by antigenemia. The high incidence and quantitative level of CCIC in patients without clinical disease suggests a role for CCIC in CMV dissemination rather than its being a specific marker of organ or tissue damage after marrow transplantation.

Adolescent↗
PubMed1997

Cytomegalovirus disease occurring before engraftment in marrow transplant recipients.

Little information is available regarding the incidence, clinical course, and response to treatment of cytomegalovirus (CMV) disease that occurs before engraftment in marrow transplant recipients. We identified 25 patients over a 12.5 year period who developed CMV disease before achieving engraftment. Twelve cases were diagnosed during life, and 13 cases were diagnosed at autopsy. The lung was the site most commonly involved (92% of patients), and most of the patients (92%) were CMV seropositive. Significant copathogens were identified in 45% of the patients. All nine patients with CMV pneumonia died within 6 weeks after the diagnosis was made, and one of two patients with gastrointestinal disease also died 6 weeks after the diagnosis was made despite the administration of antiviral therapy. Surveillance cultures were not helpful in identifying patients at risk for disease. Histopathological examination of the lungs of patients with early CMV pneumonia only infrequently showed typical CMV lesions. In conclusion, CMV disease occurring before engraftment in CMV-seropositive recipients was uncommon, was frequently associated with the presence of other opportunistic pathogens, and was associated with a high fatality rate. Better diagnostic methods to identify patients at risk are required in the preengraftment period.

Adolescent↗